WO1993007875A1 - Verwendung von prostacyclin-derivaten zur verhinderung oder behandlung von störungen der mikrozirkulation bei gabe von röntgen-, nmr- oder ultraschallkontrastmitteln - Google Patents

Verwendung von prostacyclin-derivaten zur verhinderung oder behandlung von störungen der mikrozirkulation bei gabe von röntgen-, nmr- oder ultraschallkontrastmitteln Download PDF

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Publication number
WO1993007875A1
WO1993007875A1 PCT/DE1992/000904 DE9200904W WO9307875A1 WO 1993007875 A1 WO1993007875 A1 WO 1993007875A1 DE 9200904 W DE9200904 W DE 9200904W WO 9307875 A1 WO9307875 A1 WO 9307875A1
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Prior art keywords
group
administered
nmr
microcirculation
ray
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PCT/DE1992/000904
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German (de)
English (en)
French (fr)
Inventor
Rainer Klopp
Wolfgang Niemer
Wolfgang Schippel
Werner Krause
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Schering Aktiengesellschaft
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Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to DE59209175T priority Critical patent/DE59209175D1/de
Priority to US08/232,006 priority patent/US5814301A/en
Priority to DK92922216T priority patent/DK0609336T3/da
Priority to EP92922216A priority patent/EP0609336B1/de
Priority to JP5507355A priority patent/JPH07500585A/ja
Publication of WO1993007875A1 publication Critical patent/WO1993007875A1/de
Priority to GR980400515T priority patent/GR3026324T3/el

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • prostacyclin derivatives for the prevention or treatment of disorders of the microcirculation when X-ray, NMR or
  • Contrast agents are indispensable aids in medical diagnostics. They allow ever stronger contrast in the preserved ones
  • This very useful area of application includes a large number of undesirable side effects such as changes in endothelial cells, damage to the erythrocytes, influencing the blood coagulation system, disruption of the microcirculation up to complete hemostasis, intensification of already existing disturbance of the microcirculation in the pathogenic tissue, changes in the blood-brain barrier or negative Influencing blood pressure.
  • the disturbance of the microcirculation is of particular importance.
  • the microcirculation is functionally the most important part of the circulatory system. In the area of microcirculation, mass transfer takes place.
  • the prostacyclin derivatives of the present invention significantly maintain or restore the microcirculation when administered shortly before or after an administration of X-ray, ultrasound or NMR contrast media or when administered together with the aforementioned contrast media.
  • the invention relates to the use of a prostacyclin derivative or the corresponding ⁇ -cyclodextrin clathrate or that with liposomes
  • encapsulated form for the manufacture of a medicament for the prevention or treatment of disorders of the microcirculation when X-ray, NMR or ultrasound contrast agents are administered.
  • the present invention preferably relates to the use of one or more prostacyclin derivatives of the general formula I.
  • R 1 is hydrogen or a C 1 -C 4 alkyl radical
  • X, Y independently of one another are a —CH 2 group or an oxygen atom
  • Z is hydrogen, fluorine or CN
  • W is a free or functionally modified hydroxymethylene group on the hydroxyl group, where the hydro ⁇ -y group can be ⁇ - or ⁇ -permanent,
  • D is a straight-chain or branched saturated C 1 -C 5 alkylene group
  • R 2 is a C 1 -C 2 alkyl group
  • R 3 represents a free or functionally modified hydroxy group, and if R 1 represents hydrogen, their salts with physiologically compatible bases, as well as their ⁇ , ⁇ or y-cyclodextrin clathrates and their liposome-encapsulated form or ataprost, beraprost, BW-15AU, ciprosten, CS 570, FCE 22509, Naxaprosten, RS-93427, SC 39902 or Taprosten for the manufacture of a medicament for the prevention or treatment of disorders of the microcirculation when X-ray, ultrasound or NMR contrast agents are administered.
  • the present invention particularly preferably relates to the use of the prostacyclin derivatives iloprost, iloprost clathrate, cicaprost, cicaprost clathrate, eptaloprost or eptaloprost clathrate.
  • the alkyl groups in R 1 are straight-chain or branched-chain alkyl groups with 1-4 C atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.
  • the alkyl groups R 1 can optionally be substituted by halogen atoms, methoxy, ethoxy, phenyl or (C 1 -C 2 ) dialkylamines.
  • substituents are fluorine, chlorine or bromine atoms, phenyl, dimethylamine, diethylamine, methoxy or ethoxy.
  • Preferred alkyl groups R 1 are methyl, ethyl, dimethylaminopropyl. Methyl and ethyl may be mentioned as the alkyl group R 2 .
  • the hydroxyl groups in R 3 and W can be present as free hydroxyl groups, the hydroxyl group in W preferably being ⁇ -permanent or can be functionally modified, for example by etherification or esterification.
  • Free hydroxy groups are preferred.
  • the radicals known to the person skilled in the art are suitable as ether or acyl radicals. Easily cleavable are preferred
  • Ether residues such as tetrahydropyranyl, tetrahydrofuranyl, ⁇ -ethoxyethyl, trimethylsilyl, dimethyl-tert-butylsilyl, diphenyl-tert-butylsilyl or tribenzylsilyl.
  • Acyl radicals which may be mentioned are, for example, acetyl, propionyl, or butyryl
  • Suitable alkylene groups D are straight-chain or branched saturated alkyl groups with 1-5 C atoms, for example methylene, ethylene, 1- or 2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1-methyldimethylene, 1-methyltrimethylene, 1-methyltetramethylene .
  • inorganic and organic bases are suitable, as are known to the person skilled in the art for the formation of physiologically compatible salts.
  • examples include: alkali metal hydroxides such as sodium or potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, etc.
  • the clathrates with ⁇ -, ⁇ - or ⁇ -cyclodextrin are obtained analogously to the specification WO 87/05294.
  • Preferred clathrates are those with ⁇ -cyclodextrin.
  • Liposomes are e.g. according to the method described in "Pharmacy in our time 11, 98 (1982)".
  • EP 11591 B1 describes the following pharmacological properties for prostacyclin derivatives of the formula I:
  • EP 86404 B1 describes the use of carbacyclins for the prophylaxis and therapy of ischemic attacks in the CNS system, for cytoprotection in the liver and in the pancreas, and the combination with ⁇ -blockers or diuretics.
  • WO 86/00808 discloses the cytoprotection of the kidney and the suitability of the prostacyclin derivatives of the formula I for the treatment of organs to be transplanted.
  • DE 35 26 362 A1 describes the combination of the prostacyclin derivatives of the formula I with thromboxane antagonists for use in thrombotic or thromboembolic disorders.
  • DE 36 08 088 A1 describes the clathrates of the carbacyclin derivatives of the formula I. From DE 36 31 169 A1, in addition to the administration forms described in EP 11591 B1, the topical administration form is known.
  • the disturbances in microcirculation observed when using a contrast medium in animal experiments such as a drastic reduction in blood cells perfused nodes in the microvascular network, increased aggregated erythrocytes, increased adhesions of white blood cells on the inner wall of the venules and impairment of the arteriolar vasomotion are particularly pronounced in the 2nd and 7th minute after the administration of contrast medium, which is due to the clinical experience with side effects and incidents with contrast media (so-called immediate reaction after approx. 2 min. or so-called late reaction after approx. 7 min-) coincided.
  • the claimed compounds can be administered topically or intravascularly (i.a., i.v.).
  • the contrast medium is administered intravascularly (i.a., i.v.).
  • the dose of prostacyclin derivatives is 1.6-0.0004 ⁇ g / kg body mass, preferably T, 2-0.0004 ⁇ g / kg body mass.
  • the present invention also relates to the combination of the prostacyclin derivatives with contrast agents, whereby prostacyclin derivatives and contrast agents can be present in one or in separate dose units.
  • X-ray, ultrasound and NMR contrast media are suitable for the combination.
  • Preferred contrast media for the combination are iotrolan, iopromide, iohexol, iosimide, metrizamide, salts of amidoacetic acid, iotroxinic acid, iopamidol, 5-hydroxyacetamido-2,4,6-triiodo-isophthalic acid- (2,3-dihydroxy-N-methylpropyl) ( 2hydroxyethyl) diamide, 3-carbamoyl-5- [N- (2-hydroxyethyl) acetamido] -2,4,6-triiodo-benzoic acid [(1RS, 2SR) -2,3-dihydroxy-1-hydroxymethylpropyl] amide Dispersions of iodipamide ethyl ester, gadolinium DTPA, gadolinium DOTA, the gadolinium complex of 10 [1-hydroxymethyl-2,3-dihydroxypropyl] -1,4,7-tris [(carboxy
  • Hance R Magnevist R , Omniscan R , iron or manganese porphyrin chelates, stable magnetite dispersions, dispersions of galactose microparticles with or without additives in water, a galactose solution or dispersions of
  • the dose unit of the contrast media can be 1-350 mg iodine / l for X-ray contrast media, 1-1000 ⁇ g particles / kg body weight for ultrasound contrast media and 0.01-0.5 for NMR contrast media.
  • this information can only serve as a guideline, since the dose of contrast medium depends strongly on the desired application.
  • Prostacyclin derivatives in particular those mentioned in claim 2, are suitable for the combination.
  • the dose of prostacyclin derivatives for the combination is in the range already given for the separate administration.
  • the iloprost dose is 0.8-1.6 ⁇ g iloprost / kg body mass in 2.0 ml solution / kg body mass.
  • 3 drops of this solution are used.
  • the number of experimental animals is 45 for intra-arterial administration, 25 for intravenous administration and 20 for topical administration.
  • the control animals receive physiological saline solution in the corresponding application.
  • the number of control animals is 12 for intraarterial and intravenous administration and 20 for topical administration.
  • the findings are obtained on the anesthetized animal under constant boundary conditions by combined incident-transmitted-light intravital microscopy on the exposed mesentery / intestine in thermostated bath solution.
  • the data is usually recorded in an interval of 5 min. up to 15 min prior to contrast administration. every minute after contrast administration.
  • the blood cell-perfused nodes of the intestinal microflow increase with the administration of iloprost.
  • the comparison with the untreated control shows that iloprost p.a. in the clinically significant time interval of 5 to 10 minutes.
  • Amidotrizoate significantly dampens contrast medium-induced disorders of the microcirculation and that a faster restoration of the physiological microperfusion is achieved.
  • FIG. 1 shows the percentage decrease in the blood cell perfused nodes in the microvascular network of the mesentery when the contrast agent is given compared to the initial conditions, and the effect of the iloprost administration.
  • the bar graph shows mean values x, the lines on the standard deviation S.
  • the percentage of aggregated erythrocytes in the total number of cells in the mesenteral network is greatly reduced by iloprost, i.e. accelerates the decrease in the number of aggregated erythrocytes.
  • FIG. 2 shows the percentage increase in the proportion of aggregated erythrocytes in the total number of cells in the microvascular network of the mesentery when the contrast medium was administered compared to the starting conditions, and the effect of the iloprost administration.
  • the animal groups 1 and 2 were treated as in the previous experiment.
  • the mean values or standard deviation are represented as in FIG. 1.
  • FIG. 3 shows the number of adhering blood cells on a defined inner wall surface of the mesentery as a function of time. Animal groups 1 and 2 were treated as in the previous experiment. The mean values or standard deviation are represented as in FIG. 1. Example 2
  • a body-warm bolus diatrizoate / urografin with 600 mg J / kg body mass is injected once.
  • the injection time is 30s.
  • Iloprost is applied for 5 minutes. after administration of contrast medium, with intravascular application on the same injection route as the contrast medium or with topical application via intestine / mesentery.
  • the iloprost dose is 1.6-0.0004 ⁇ g iloprost / kg body mass in 2.0 ml solution / kg body mass.
  • 3 drops of this solution are used.
  • Physiological saline solution with the appropriate volume is applied as a reference substance. Due to the small differences in the body mass of the test animals, an almost identical bolus volume of approx. 1 ml can be applied to all test animals. The number of experimental animals is 10 per treatment group.
  • erythrocyte aggregation Number of aggregated erythrocytes in the microvascular flow bed (%, percentage of aggregated erythrocytes in the total number of cells in the observed flow bed; as erythrocyte aggregation, a longer attachment of at least 2 to 3 erythrocytes is observed, the different types of aggregation not being differentiated);
  • the measured variables are determined in micro vessels with diameters ⁇ 40 ⁇ m.
  • the measurements of the microcirculatory features are carried out on the mesentery of the interstinum pneumonia and the mucous membrane of the intestinum *** itself in complete, identical segments.
  • the intestine is surgically exposed on the anesthetized and thermostated animal and stored in a bath solution thermostatted to the core of the body (equivalent to the intraperitoneal fluid).
  • the representation of the microvascular network takes place with the help of an intravital microscopic examination unit in the combined
  • Incident light transmitted light procedure on the uninjured organ with computer-assisted image processing and processing The vital microscopic findings are carried out under constant macrocirculatory boundary conditions.
  • an orienting overview of the complete microvascular network of the entire mesenteric or intestinal segment is obtained - including its further inflows and outflows, branching geometry and hierarchy and functional vessel identification.
  • the anatomical vascular identification in the colored histological specimen is carried out after the end of the test as part of the final histopathological examination of all test animals.
  • the data is usually recorded in an interval of 5 min. before the contrast medium up to 10 min - after the contrast medium every minute.
  • the number of nodes perfused with blood cells increases more rapidly with the administration of iloprost.
  • the proportion of aggregated erythrocytes in the total number of blood cells in the network decreases more rapidly after administration of iloprost.
  • the number of blood cells adhering to the inner wall of the venule decreases due to iloprost.
  • x denotes the mean, UG the lower limit and OG the upper limit of the confidence interval.
  • the frequency spectrum of the arteriolar vasomotion shows smaller deviations from the normal state due to the administration of iloprost than when exclusive use of contrast media (see Figure 4-6).
  • FIG. 6 shows the frequency spectrum of an animal which was administered iloprost at a dose of 0.8 ⁇ g / kg 5 minutes after intravenous administration of diatrizoate on the same injection route after 7 minutes
  • Contrast agent administration ie in the 2nd minute after iloprost injection.
  • a microcathedral for intravascular injection of the contrast medium is either in the common carotid artery. advanced to the aortic arch (intra-arterial injection) or inserted into the femoral vein (intravenous injection).
  • a one-time injection of a body-warm bolus diatrizoate / urografin with 600 mg J / kg body mass is carried out.
  • the injection time is 30s.
  • Iloprost is administered at the same time as the contrast medium, in the case of intravascular application on the same injection route as the contrast medium or in the case of topical application via intestine / mesentery.
  • the dose of Iloprost is. 1.6-0.0004 ⁇ g iloprost / kg body mass in 2.0 ml solution / kg body mass.
  • 3 drops of this solution are used.
  • Physiological saline solution with the appropriate volume is applied as a reference substance. Due to the small differences in the body mass of the test animals, an almost identical bolus volume of approx. 1 ml can be applied to all test animals.
  • the number of experimental animals is 10 per treatment group.
  • the measured variables are in microvessels with a diameter of approx. 45 ⁇ m at a specific location every second in an approx. 15-minute observation interval; Determination of the amplitude-frequency spectrum of the vasomotion vibration).
  • the measured variables are determined in micro vessels with diameters ⁇ 40 ⁇ m.
  • the measurements of the microcirculatory features are carried out on the mesentery of the interstinum pneumonia and the mucosa of the intestinum *** itself in complete, identical segments.
  • the intestine is surgically exposed on the anesthetized and thermostatted animal and stored in a bath solution that is thermally warmed to the core (equivalent to intraperitoneal fluid).
  • the microvascular network is displayed using an intravital microscopic examination unit in a combined incident-transmitted light procedure on the uninjured organ with computer-assisted image processing and processing.
  • the vital microscopic findings are carried out under constant macrocirculatory boundary conditions.
  • an orienting overview of the complete microvascular network of the entire mesenteric or intestinal segment is obtained - including its further inflows and outflows, branching geometry and hierarchy and functional vessel identification.
  • the anatomical vascular identification in the colored histological specimen is carried out after the end of the test as part of the final histopathological examination of all test animals.
  • the data is usually recorded in an interval of 5 min. up to 10 min prior to contrast administration. every minute after contrast administration.
  • the number of nodes perfused with blood cells increases more rapidly with the administration of iloprost.
  • the proportion of aggregated erythrocytes in the total number of blood cells in the network decreases more rapidly after administration of iloprost.
  • the number of blood cells adhering to the inner wall of the venule decreases due to iloprost.
  • the following table shows measurement results for the findings described above in the microvascular network of the mucosa of the intestinal um.
  • One group of animals was injected with a diatrizoate bolus (column 1), a second group received intravenous administration of 0.8 ⁇ g / kg iloprost at the same time as the injection of the diatrizoate bolus (column 2).
  • x denotes the mean, UG the lower limit and OG the upper limit of the confidence interval.
  • the frequency spectrum of the arteriolar vasomotion shows smaller deviations from the normal state due to the administration of iloprost than with the exclusive application of contrast media.

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PCT/DE1992/000904 1991-10-22 1992-10-22 Verwendung von prostacyclin-derivaten zur verhinderung oder behandlung von störungen der mikrozirkulation bei gabe von röntgen-, nmr- oder ultraschallkontrastmitteln WO1993007875A1 (de)

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Application Number Priority Date Filing Date Title
DE59209175T DE59209175D1 (de) 1991-10-22 1992-10-22 Verwendung von prostacyclin-derivaten zur verhinderung oder behandlung von störungen der mikrozirkulation bei gabe von röntgen-, nmr- oder ultraschallkontrastmitteln
US08/232,006 US5814301A (en) 1991-10-22 1992-10-22 Use of prostacyclin derivatives to prevent or to treat disorders of the microcirculatory system when x-ray, NMR or ultrasonic contrast media are administered
DK92922216T DK0609336T3 (da) 1991-10-22 1992-10-22 Anvendelse af prostacyclin-derivater til forebyggelse eller behandling af lidelser i mikrocirkulationssystemet ved administ
EP92922216A EP0609336B1 (de) 1991-10-22 1992-10-22 Verwendung von prostacyclin-derivaten zur verhinderung oder behandlung von störungen der mikrozirkulation bei gabe von röntgen-, nmr- oder ultraschallkontrastmitteln
JP5507355A JPH07500585A (ja) 1991-10-22 1992-10-22 造影剤の副作用を防止するか又は治療するためのプロスタサイクリン誘導体の使用
GR980400515T GR3026324T3 (en) 1991-10-22 1998-03-11 Use of prostacyclin derivatives to prevent or treat disorders of the microcirculating system when x-ray, nmr or ultrasonic contrasting agents are administered.

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DE4135193A DE4135193C1 (enrdf_load_stackoverflow) 1991-10-22 1991-10-22
DEP4135193.2 1991-10-22

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US (1) US5814301A (enrdf_load_stackoverflow)
EP (1) EP0609336B1 (enrdf_load_stackoverflow)
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AT (1) ATE162718T1 (enrdf_load_stackoverflow)
CA (1) CA2121838A1 (enrdf_load_stackoverflow)
DE (2) DE4135193C1 (enrdf_load_stackoverflow)
DK (1) DK0609336T3 (enrdf_load_stackoverflow)
ES (1) ES2114570T3 (enrdf_load_stackoverflow)
GR (1) GR3026324T3 (enrdf_load_stackoverflow)
PT (1) PT100997B (enrdf_load_stackoverflow)
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US9066990B2 (en) 2001-03-26 2015-06-30 Bayer Intellectual Property Gmbh Preparation for restenosis prevention
US9649476B2 (en) 2002-09-20 2017-05-16 Bayer Intellectual Property Gmbh Medical device for dispersing medicaments

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DE4446694A1 (de) * 1994-12-09 1996-06-13 Schering Ag Verwendung von Zusätzen zu Kontrastmitteln zur Verbesserung der Bildgebung
US6774278B1 (en) 1995-06-07 2004-08-10 Cook Incorporated Coated implantable medical device
CN1209751A (zh) * 1996-01-25 1999-03-03 舍林股份公司 血管内使用的改进的浓缩注射液和输注液
ATE262336T1 (de) * 1997-11-14 2004-04-15 United Therapeutics Corp Verwendung von 9-desoxy-2',9-alpha-methano-3-oxa- 4,5,6-trinor-3,7-(1',3'-interphenylen)-13,14- dihydroprostaglandin-f1 zur behandlung von peripheren vaskulären erkrankungen
US20020147223A1 (en) * 1999-06-14 2002-10-10 Hiroshi Maeda Agent for enhancing accumulation of drugs in tumor tissues
EP1628654B2 (en) 2003-05-22 2019-12-04 United Therapeutics Corporation Compounds and methods for delivery of prostacyclin analogs
CN101287457B (zh) * 2004-04-12 2011-11-16 联合治疗公司 Treprostinil用于治疗神经性糖尿病的足部溃疡的用途
CA3212313A1 (en) 2013-03-14 2014-10-02 United Therapeutics Corporation Solid forms of treprostinil
MX2021001820A (es) * 2018-09-14 2021-04-28 Pharmosa Biopharm Inc Composicion farmaceutica para la liberacion controlada de farmacos acidos debiles y usos de los mismos.

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PT100997B (pt) 1999-10-29
CA2121838A1 (en) 1993-04-29
US5814301A (en) 1998-09-29
EP0609336A1 (de) 1994-08-10
ES2114570T3 (es) 1998-06-01
PT100997A (pt) 1994-01-31
EP0609336B1 (de) 1998-01-28
DE4135193C1 (enrdf_load_stackoverflow) 1993-03-11
JPH07500585A (ja) 1995-01-19
ATE162718T1 (de) 1998-02-15
GR3026324T3 (en) 1998-06-30
DE59209175D1 (de) 1998-03-05

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